Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an ultra-rare, progressive genetic disease, characterised by immune deficiency and dysregulation, affecting individuals from birth. In a 12-week phase III randomised placebo-controlled trial, leniolisib, a selective PI3Kδ inhibitor, was well-tolerated and met both co-primary endpoints (change from Baseline in log10-transformed sum of product of diameters of index lymph nodes and percentage of naïve/total B cells at Day 85). Here, prespecified subgroup analyses are reported in adolescents aged 12-17 years (leniolisib, n = 8; placebo, n = 4) and adults aged ≥18 (leniolisib, n = 13; placebo, n = 6). In both subgroups, leniolisib reduced lymphadenopathy (least squares mean change versus placebo: adolescents, -0.4 versus -0.1; adults, -0.3 versus 0.1) and increased the percentage of naïve B cells (least squares mean change: adolescents, 44.5 versus -16.5; adults, 28.4 versus -1.1). Leniolisib was well-tolerated in both adolescents and adults. These results show leniolisib is an effective APDS treatment in both subpopulations. PLAIN LANGUAGE SUMMARY: What is activated PI3Kδ syndrome (APDS)? APDS is an ultra-rare disease in which the immune system does not work correctly. People with APDS have a wide range of symptoms, including infections, certain organs associated with the immune system becoming larger, and worse quality of life. These symptoms generally start in childhood. Why was this study carried out? Current treatments only treat the symptoms of APDS, rather than correcting the cause of the problem. These treatments can also have significant side effects. A new medication for APDS called leniolisib aims to treat the underlying cause of the disease. This publication reports results from a clinical trial of leniolisib which compared patients who received leniolisib with patients who received a placebo. The aim of this report was to examine these clinical trial results to understand if leniolisib is effective and safe when treating both adolescents (12-17 years old) and adults (18 years and older) with APDS. What were the results of this study? Leniolisib improved the number of certain immune cells, compared to patients who did not receive leniolisib, in both adolescents and adults with APDS. Leniolisib also reduced the size of the enlarged immune system organs in both adolescents and adults with APDS. There were no major safety concerns for either age group who received leniolisib. What do these results mean? These results show that leniolisib can help the immune system to work in a way that is closer to those without APDS. This new treatment is effective and generally well-tolerated for both adolescents and adults. These results indicate that people with APDS are able to start treatment with leniolisib during adolescence, which may slow the build-up of symptoms and may also have a positive impact on the quality of their lives.

• Klíčová slova
• APDS, Adolescents, Leniolisib, PASLI, PI3K, Pediatric, Subgroups,
• MeSH
• B-lymfocyty imunologie   účinky léků   MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fosfatidylinositol-3-kinasy třídy I * genetika   antagonisté a inhibitory   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• primární imunodeficience * farmakoterapie   genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• fosfatidylinositol-3-kinasy třídy I * MeSH
• PIK3CD protein, human MeSH Prohlížeč

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life (HRQoL) assessed through a clinician-reported questionnaire. We observed improvements in HRQoL: 5 of 6 patients experienced an increase in physical capabilities and socialization, and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated after year 2, with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4/5 nor deemed leniolisib related. Collectively, we saw an enhancement in HRQoL as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. This trial was registered at www.ClinicalTrials.gov as #NCT02859727.

• MeSH
• dospělí MeSH
• fosfatidylinositol-3-kinasy třídy I * antagonisté a inhibitory   MeSH
• inhibitory fosfoinositid-3-kinasy terapeutické užití   farmakologie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• primární imunodeficience * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fosfatidylinositol-3-kinasy třídy I * MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• PIK3CD protein, human MeSH Prohlížeč